This experimental study was conducted in the
inpatient detoxification addictive behavior unit
of the Sant Pau Hospital in Barcelona and
included 22 healthy subjects (HS) and 42
intravenous heroin-dependent subjects (HDS).
Apomorphine-induced yawning rates were
investigated in three different groups;
heroin-dependent patients stabilized on
d-propoxiphene, heroin-dependent patients
recently withdrawn from d-propoxiphene and
normal controls. Yawning responses were recorded
continuously by independent observers for
periods of 45 minutes following administration
of low doses of subcutaneous apomorphine and
NaCl. The lowest subcutaneous apomorphine dose
able to induce a significantly higher number of
yawning responses in HS was 0.005 mg/kg. The
yawning responses induced by this dose in HDS
were also significantly higher than those
induced by placebo. When comparing the number of
yawning responses between the study groups,
differences were observed only between HDS and
HS and no effect of gender was obtained. The
apomorphine test may be useful in assessing
central dopamine system alterations associated
with chronic heroin consumption and could be a
stable and reliable biological marker of
heroin-dependence disorders.

Introduction

Changes in the sensitivity of the
mesothelencephalic dopamine system have been
related extensively to opiate reinforcement,
withdrawal and craving. Yawning induced by low
doses of apo- morphine (apomorphine test) is
frequently in neurology to evaluate the
responsiveness of dopamine systems in
Parkinsonian patients. Furthermore, it is an
easy and ethical procedure to assess the
sensitivity of the dopaminergic system in
humans. Apomorphine-induced yawning is mediated
centrally, possibly by the stimulation of a
subpopulation of postsynaptic D2 or D3 dopamine
receptors. In a preliminary pilot study,
heroin-dependent subjects (HDS) showed a greater
number of apomorphine induced yawns than healthy
volunteers, suggesting the apomorphine test
could be useful in assessing dopaminergic system
sensitivity in HDS.

To extend our previous work, the main aim
was to confirm that the apomorphine-induced
yawning responses are not only associated to a
temporary stage of stabilization with an opiate
agonist or to an opiate post-withdrawal stage
but to the presence of a heroin-dependence
disorder. In the present study, the apomorphine
test was performed at two different times during
the recovery process of heroin-dependent
patients. Previously, a study to identify the
lowest apomorphine dose able to induce yawning
in HS was performed. The apomorphine response
was then assessed in the two different HDS
groups compared to healthy subjects (HS), also
analysing possible gender differences.

Discussion

Some studies were performed with higher
doses of apomorphine. We performed a previous
dose response study in order to set more
accurately the optimal apomorphine dose able to
induce yawning responses without inducing
adverse events (such as nausea) at the same
time. Although other lower doses of apomorphine
can also have a certain yawning inducing effect,
0.005 mg/kg is the most appropriate dose because
it induced more yawning responses and no adverse
events.

We found no significant effect of gender or
interaction effect of group x gender, gender
xsubstance and group x sender x substance. No
gender differences were round in any group
either in placebo-induced or in
apomorphine-induced yawns. Therefore as other
authors have found we can conclude that there
are no gender differences in apomorphine induced
yawning responses. Even though 0.005 mg/kg
apomorphine induced significantly more yawns
than placebo in all groups, a significantly
greater number of apomorphine induced yawns was
obtained in the HDS as compared to HS. This
result confirms previous findings and suggests
that HDS might have an altered dopaminergic
sensitivity in brain areas involving yawning,
such as the striatum.

As an altered sensitivity of the dopamine
system in striatal areas has been related to
several aspects of heroin dependence, the
apomorphine test could be a simple non-invasive
procedure to determine the sensitivity of the
dopaminergic neurotransmission in HMS. The fact
that no differences were observed between
stabilized HDS and detoxified HDS suggests that
changes in dopaminergic sensitivity assessed
with the apomorphine test in HDS are not
influenced by the administration of opioid
agonists and are maintained during short-term
abstinence in such patients.

Therefore, the apomorphine test can be
considered as a stable biological marker of
heroin dependence disorder. Moreover, as changes
in dopaminergic sensitivity were also determined
by other proceedings in other
substance-dependence disorders, such as cocaine
or alcohol dependence, the potential usefulness
of the apomorphine test as a biological marker
for drug dependence should be studied further.

In future the apomophine test could improve
diagnosis prognosis and pharmacotherapy of
substancedependence disorders.